Experimental Conditions to Retrieve Intrinsic Cooperativity α Directly from Single Binding Assay Data Exemplified by the Ternary Complex Formation of FKBP12, MAPRE1 and Macrocyclic Molecular Glues

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 2936 - 2936

Опубликована: Март 24, 2025

The incorporation of disease-relevant targets into ternary complexes in a compound-dependent manner by utilizing an assisting chaperone has become common modality as far bifunctional complex-forming compounds are concerned. In contrast, examples formed molecular glues much rarer. Due to their lack significant binary (independent) target affinity, identification cannot yet be achieved rational methods and is, therefore, more challenging. However, it is precisely for that reason (given the associated advantages) systematic application drug discovery recently attracted particular interest. contrast compounds, retrieve part thermodynamic stability through newly induced chaperone-target or glue-target interactions occur only complex. These lead enhanced ligand binding-termed intrinsic cooperativity α-which can retrieved via apparent either monitoring binding protein. this publication, advantage measuring (to determine α) weaker protein discussed illustrated using example between FKBP12, MAPRE1 macrocyclic derived from rapamycin motif FKBP12. Furthermore, impact following three parameters on illustrated: (1) concentration protein, (2) excess counter (3) affinity glue combination with degree α. From this, experimental conditions α one assay without need comprehensive mathematical model covering all simultaneous events under non-saturating highlighted. framework requires capable at least estimating very weak affinities. If not possible reasons, but assays both proteins available within normal bandwidth stronger too high, how curve presence used overcome missing Kd weakly

Язык: Английский

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From Traditional Methods to Deep Learning Approaches: Advances in Protein–Protein Docking

Wiley Interdisciplinary Reviews Computational Molecular Science, Год журнала: 2025, Номер 15(2)

Опубликована: Март 1, 2025

ABSTRACT Protein–protein interactions play a crucial role in human biological processes, and deciphering their structural information interaction patterns is essential for drug development. The high costs of experimental structure determination have brought computational protein–protein docking methods into the spotlight. Traditional algorithms, which hinge on sampling‐scoring framework, heavily rely extensive sampling candidate poses customized scoring functions based geometric chemical compatibility between proteins. However, these face challenges related to efficiency stability. advent deep learning (DL) has ushered data‐driven that demonstrate significant advantages, particularly boosting docking. We systematically review historical development from traditional approaches DL techniques provide insights emerging technologies this field. Moreover, we summarize commonly used datasets evaluation metrics expect can offer valuable guidance more efficient algorithms.

Язык: Английский

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Advancing target validation with PROTAC technology

Expert Opinion on Drug Discovery, Год журнала: 2025, Номер unknown

Опубликована: Апрель 5, 2025

Targeted protein degradation (TPD) is a cutting-edge technology that provides new avenues for drug discovery and development. PROteolysis TArgeting Chimeras (PROTACs) are the most established advanced TPD strategy, enabling selective of disease-associated 'undruggable' proteins interest (POIs) by leveraging cell's natural machinery. To confirm PROTAC-induced proximity drives degradation, target validation ternary complex formation must be thoroughly assessed. In this perspective, authors detail some widely used in silico, structural, vitro, cellulo methods to validate PROTAC engagement formation. Additionally, they discuss growing use PROTACs as chemical probes novel identification validation. Target essential approach, ongoing studies should prioritize confirming using assays conducted under physiologically relevant cellular conditions. The believe proteomics analyses among valuable tools elucidating mechanism, selectivity, outcomes PROTACs. They also remain optimistic about future development their engagement. While rapidly advancing, it still holds vast opportunities exploration, offering significant potential further both biological research drive drugs.

Язык: Английский

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Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the Design of VHL‐Mediated PROTACs Targeting the Kinase FLT3

Archiv der Pharmazie, Год журнала: 2025, Номер 358(4)

Опубликована: Апрель 1, 2025

ABSTRACT Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease‐causing proteins in drug discovery. One E3 ligases which efficient PROTACs been described is Von Hippel‐Lindau factor (VHL). However, development has so far often relied on minimum computational tools, that it mostly based trial‐and‐error process. Therefore, there great need resource‐ and time‐efficient structure‐based or approaches streamline PROTAC design. In this study, we present combined integrates static ternary complex formation, induced‐fit docking, molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived structures VHL PROTACs, reported BRD4, SMARCA2, FAK, WEE1. addition, applied validated model recently in‐house developed FLT3‐targeted (MA49). The results show models generated with protein–protein docking method implemented software MOE high predictive power reproducing experimental 3D structures. different active their respective showed reliability new VHL‐mediated degraders. particular, sensitive structural changes as evidenced by failed binding modes negative controls. Furthermore, MD simulations confirmed stability complexes emphasized importance dynamic studies understanding relationship between structure function.

Язык: Английский

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Targeted Degradation of Structured RNAs via Ribonuclease-Targeting Chimeras (RiboTacs)

Expert Opinion on Drug Discovery, Год журнала: 2023, Номер 18(8), С. 929 - 942

Опубликована: Июнь 12, 2023

RNA structural motifs can serve as recognition sites for proteins or regulatory elements. Notably, these specific shapes are directly related to many diseases. Targeting using small molecules is an emerging domain of study within the area drug discovery. Targeted degradation strategies a relatively modern technology in discovery, offering important clinical and therapeutic outcomes. These approaches involve selectively degrade biomacromolecules associated with disease. "Ribonuclease-Targeting Chimeras" (RiboTaCs) represent promising type targeted strategy due their ability structured targets.In this review, authors present evolution RiboTaCs, underlying mechanism, in-vitro validation. The summarize several disease-associated RNAs that have been previously RiboTaC discuss how led alleviating phenotypes in-vivo.There future challenges still need be adressed fully realize its potential. Despite challenges, optimistic about prospects, which potential fundamentally transform treatment wide range

Язык: Английский

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Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

Bioconjugate Chemistry, Год журнала: 2024, Номер 35(8), С. 1089 - 1115

Опубликована: Июль 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Язык: Английский

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Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(8), С. 1306 - 1318

Опубликована: Июль 29, 2024

Protein degraders, such as bifunctional proteolysis-targeting chimeras (PROTACs), selectively eliminate target proteins by leveraging the natural protein degradation machinery. PROTACs bridge with an E3 ligase, which induces ubiquitination and degradation. Investigating ternary complex structures elucidates molecular mechanisms of their formation This study examines binding dynamics ligases (VHL, CRBN, cIAP) interest, focusing on dynamics, cooperativity, selectivity, linker length, PROTAC conformations. The influence interface residues lengths specific conformations for is highlighted. Utilizing steered simulations, provides comprehensive parameters behavior stability diverse complexes. These insights are crucial designing targeting disease-causing advancing development degradable complexes therapeutic applications.

Язык: Английский

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Next steps for targeted protein degradation

Cell chemical biology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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DegraderTCM: A Computationally Sparing Approach for Predicting Ternary Degradation Complexes

ACS Medicinal Chemistry Letters, Год журнала: 2023, Номер 15(1), С. 45 - 53

Опубликована: Дек. 13, 2023

Proteolysis targeting chimeras (PROTACs or degraders) represent a novel therapeutic modality that has raised interest thanks to promising results and currently undergoing clinical testing. PROTACs induce the selective proteasomal degradation of undesired proteins by formation ternary complexes (TCs). Having knowledge 3D structure TCs is crucial for design PROTAC drugs. Here, we describe DegraderTCM, new computational method modeling PROTAC-mediated requires low power provides sound in short time span. We validated DegraderTCM against selected set experimentally determined structures defined predict activity based on computed TC structure. Finally, modeled known degraders holding significance defining method's applicability domain. A retrospective analysis structure–activity relationships unveiled possibilities utilizing initial stages designing

Язык: Английский

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Chemical rewiring of ubiquitination by degraders and their selectivity routes

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(2), С. 205 - 207

Опубликована: Фев. 1, 2024

Язык: Английский

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